The metabolic oncogene fatty acid synthase (FASN) is overexpressed in 80% of ovarian cancers (OC) and indicates poor prognosis. Exposure of OC to inhibitors of FASN elicits a complex stress response that interferes with receptor-PI3K-mTORC1 signaling (briefly designated 'PI3K pathway'). Here we demonstrate that FASN inhibitors capitalize on multiple mechanisms to interfere with the PI3K pathway, and that silencing this cascade is crucial for the anticancer action of the drugs.